Prenylated Coumaric Acids from Artemisia scoparia Beneficially Modulate Adipogenesis.

Two new diprenylated coumaric acid isomers (1a and 1b) and two known congeners, capillartemisin A (2) and B (3), were isolated from Artemisia scoparia as bioactive markers using bioactivity-guided HPLC fractionation. Their structures were determined by spectroscopic means, including 1D and 2D NMR methods and LC-MS, with their purity assessed by 1D 1H pure shift qNMR spectroscopic analysis. The bioactivity of compounds was evaluated by enhanced accumulation of lipids, as measured using Oil Red O staining, and by increased expression of several adipocyte marker genes, including adiponectin in 3T3-L1 adipocytes relative to untreated negative controls. Compared to the plant's 80% EtOH extract, these purified compounds showed significant but still weaker inhibition of TNFα-induced lipolysis in 3T3-L1 adipocytes. This suggests that additional bioactive substances are responsible for the multiple metabolically favorable effects on adipocytes observed with Artemisia scoparia extract.

Artemisia scoparia and Metabolic Health: Untapped Potential of an Ancient Remedy for Modern Use.

Botanicals have a long history of medicinal use for a multitude of ailments, and many modern pharmaceuticals were originally isolated from plants or derived from phytochemicals. Among these, artemisinin, first isolated from Artemisia annua, is the foundation for standard anti-malarial therapies. Plants of the genus Artemisia are among the most common herbal remedies across Asia and Central Europe. The species Artemisia scoparia (SCOPA) is widely used in traditional folk medicine for various liver diseases and inflammatory conditions, as well as for infections, fever, pain, cancer, and diabetes. Modern in vivo and in vitro studies have now investigated SCOPA's effects on these pathologies and its ability to mitigate hepatotoxicity, oxidative stress, obesity, diabetes, and other disease states. This review focuses on the effects of SCOPA that are particularly relevant to metabolic health. Indeed, in recent years, an ethanolic extract of SCOPA has been shown to enhance differentiation of cultured adipocytes and to share some properties of thiazolidinediones (TZDs), a class of insulin-sensitizing agonists of the adipogenic transcription factor PPARγ. In a mouse model of diet-induced obesity, SCOPA diet supplementation lowered fasting insulin and glucose levels, while inducing metabolically favorable changes in adipose tissue and liver. These observations are consistent with many lines of evidence from various tissues and cell types known to contribute to metabolic homeostasis, including immune cells, hepatocytes, and pancreatic beta-cells. Compounds belonging to several classes of phytochemicals have been implicated in these effects, and we provide an overview of these bioactives. The ongoing global epidemics of obesity and metabolic disease clearly require novel therapeutic approaches. While the mechanisms involved in SCOPA's effects on metabolic, anti-inflammatory, and oxidative stress pathways are not fully characterized, current data support further investigation of this plant and its bioactives as potential therapeutic agents in obesity-related metabolic dysfunction and many other conditions.

Mechanisms of Artemisia scoparia's Anti-Inflammatory Activity in Cultured Adipocytes, Macrophages, and Pancreatic ß-Cells.

OBJECTIVE: An ethanolic extract of Artemisia scoparia (SCO) improves adipose tissue function and reduces negative metabolic consequences of high-fat feeding. A. scoparia has a long history of medicinal use across Asia and has anti-inflammatory effects in various cell types and disease models. The objective of the current study was to investigate SCO's effects on inflammation in cells relevant to metabolic health. METHODS: Inflammatory responses were assayed in cultured adipocytes, macrophages, and insulinoma cells by quantitative polymerase chain reaction, immunoblotting, and NF-κB reporter assays. RESULTS: In tumor necrosis factor α-treated adipocytes, SCO mitigated ERK and NF-κB signaling as well as transcriptional responses but had no effect on fatty acid-binding protein 4 secretion. SCO also reduced levels of deleted in breast cancer 1 protein in adipocytes and inhibited inflammatory gene expression in stimulated macrophages. Finally, in pancreatic ß-cells, SCO decreased NF-κB-responsive promoter activity induced by IL-1ß treatment. CONCLUSIONS: SCO's ability to promote adipocyte development and function is thought to mediate its insulin-sensitizing actions in vivo. Our findings that SCO inhibits inflammatory responses through at least two distinct signaling pathways (ERK and NF-κB) in three cell types known to contribute to metabolic disease reveal that SCO may act more broadly than previously thought to improve metabolic health.

An ethanolic extract of Artemisia scoparia inhibits lipolysis in vivo and has antilipolytic effects on murine adipocytes in vitro.

An ethanolic extract of Artemisia scoparia (SCO) has metabolically favorable effects on adipocyte development and function in vitro and in vivo. In diet-induced obese mice, SCO supplementation significantly reduced fasting glucose and insulin levels. Given the importance of adipocyte lipolysis in metabolic health, we hypothesized that SCO modulates lipolysis in vitro and in vivo. Free fatty acids and glycerol were measured in the sera of mice fed a high-fat diet with or without SCO supplementation. In cultured 3T3-L1 adipocytes, the effects of SCO on lipolysis were assessed by measuring glycerol and free fatty acid release. Microarray analysis, qPCR, and immunoblotting were used to assess gene expression and protein abundance. We found that SCO supplementation of a high-fat diet in mice substantially reduces circulating glycerol and free fatty acid levels, and we observed a cell-autonomous effect of SCO to significantly attenuate tumor necrosis factor-α (TNFα)-induced lipolysis in cultured adipocytes. Although several prolipolytic and antilipolytic genes were identified by microarray analysis of subcutaneous and visceral adipose tissue from SCO-fed mice, regulation of these genes did not consistently correlate with SCO's ability to reduce lipolytic metabolites in sera or cell culture media. However, in the presence of TNFα in cultured adipocytes, SCO induced antilipolytic changes in phosphorylation of hormone-sensitive lipase and perilipin. Together, these data suggest that the antilipolytic effects of SCO on adipose tissue play a role in the ability of this botanical extract to improve whole body metabolic parameters and support its use as a dietary supplement to promote metabolic resiliency.

Screening native botanicals for bioactivity: an interdisciplinary approach.

OBJECTIVE: Plant-based therapies have been used in medicine throughout recorded history. Information about the therapeutic properties of plants often can be found in local cultures as folk medicine is communicated from one generation to the next. The aim of this study was to identify native Louisiana plants from Creole folk medicine as a potential source of therapeutic compounds for the treatment of insulin resistance, type 2 diabetes, and related disorders. METHODS: We used an interdisciplinary approach combining expertise in disciplines ranging from cultural anthropology and botany to biochemistry and endocrinology to screen native southwest Louisiana plants. Translation of accounts of Creole folk medicine yielded a list of plants with documented use in treating a variety of conditions, including inflammation. These plants were collected, vouchered, and catalogued before extraction of soluble components. Extracts were analyzed for bioactivity in regulating inflammatory responses in macrophages or fatty acid-induced insulin resistance in C2C12 skeletal muscle cells. RESULTS: Several extracts altered gene expression of inflammatory markers in macrophages. Multiplex analysis of kinase activation in insulin-signaling pathways in skeletal muscle also identified a subset of extracts that alter insulin-stimulated protein kinase B phosphorylation in the presence of fatty-acid-induced insulin resistance. CONCLUSION: An interdisciplinary approach to screening botanical sources of therapeutic agents can be successfully applied to identify native plants used in folk medicine as potential sources of therapeutic agents in treating insulin resistance in skeletal muscle or inflammatory processes associated with obesity-related insulin resistance.

Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome.

OBJECTIVE: In preclinical reports, restriction of dietary methionine intake was shown to enhance metabolic flexibility, improve lipid profiles, and reduce fat deposition. The present report is the outcome of a "proof of concept" study to evaluate the efficacy of dietary methionine restriction (MR) in humans with metabolic syndrome. METHODS: Twenty-six obese subjects (six male and 20 female) meeting criteria for metabolic syndrome were randomized to a diet restricted to 2 mg methionine/kg body weight per day and were provided capsules containing either placebo (n = 12) or 33 mg methionine/kg body weight per day (n = 14). Energy expenditure, body composition, insulin sensitivity, and biomarkers of metabolic syndrome were measured before and after 16 wk on the respective diets. RESULTS: Insulin sensitivity and biomarkers of metabolic syndrome improved comparably in both dietary groups. Rates of energy expenditure were unaffected by the diets, but dietary MR produced a significant increase in fat oxidation (MR, 12.1 ± 6.0% increase; control, 8.1 ± 3.3% decrease) and reduction in intrahepatic lipid content (MR liver/spleen attenuation ratio, 8.1 ± 3.3% increase; control ratio, 2.2 ± 2.1% increase) that was independent of the comparable reduction in weight and adiposity that occurred in both groups. CONCLUSIONS: Sixteen weeks of dietary MR in subjects with metabolic syndrome produced a shift in fuel oxidation that was independent of the weight loss, decreased adiposity, and improved insulin sensitivity that was common to both diets.

Role of beta-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction.

Dietary methionine restriction (MR) limits fat deposition and decreases plasma leptin, while increasing food consumption, total energy expenditure (EE), plasma adiponectin, and expression of uncoupling protein 1 (UCP1) in brown and white adipose tissue (BAT and WAT). beta-adrenergic receptors (beta-AR) serve as conduits for sympathetic input to adipose tissue, but their role in mediating the effects of MR on energy homeostasis is unclear. Energy intake, weight, and adiposity were modestly higher in beta(3)-AR(-/-) mice on the Control diet compared with wild-type (WT) mice, but the hyperphagic response to the MR diet and the reduction in fat deposition did not differ between the genotypes. The absence of beta(3)-ARs also did not diminish the ability of MR to increase total EE and plasma adiponectin or decrease leptin mRNA, but it did block the MR-dependent increase in UCP1 mRNA in BAT but not WAT. In a further study, propranolol was used to antagonize remaining beta-adrenergic input (beta(1)- and beta(2)-ARs) in beta(3)-AR(-/-) mice, and this treatment blocked >50% of the MR-induced increase in total EE and UCP1 induction in both BAT and WAT. We conclude that signaling through beta-adrenergic receptors is a component of the mechanism used by dietary MR to increase EE, and that beta(1)- and beta(2)-ARs are able to substitute for beta(3)-ARs in mediating the effect of dietary MR on EE. These findings are consistent with the involvement of both UCP1-dependent and -independent mechanisms in the physiological responses affecting energy balance that are produced by dietary MR.